REVIEW
Quinolone resistance and Cumpylobucter Clirz Microbial Infect 1999; 5: 239-243
Laura]. V Piddock Antimicrobial Agents Research Group, Division of Immunity and Infection, T h e Medical School, University of Birmingham, Birmingham, UK Key words: Campylobacter, fluoroquinolone resistance
[lo]. However, there is clear evidence that microbiological eradication is no quicker in the presence of fluoroquinolone therapy [I 11. Resistance of Campylobacter strains to fluoroquinolone antimicrobials has been recognized for several years, and emergence of resistance after fluoroquinolone therapy in humans has also been reported [12]. The MIC of ciprofloxacin for these bacteria ranges from 32 to 256 mg/L. Quinoloneresistant Campylobactev strains are being isolated with increasing frequency in several European countries [12].
Contaminated food is the usual source of human campylobacter infection (predominantly Campylobacter jejuni and C. coli) [1,2], and the presence of fluoroquinolone-resistant strains in the food chain has raised concerns that the human disease, which responds to oral quinolones such as ciprofloxacin, will be compromised. However, because of the low mortality and self-limiting nature of campylobacter enteritis, many would consider quinolone therapy to be unjustified unless the patient is immunocompromised or the infection is extraintestinal. The majority of infections are sporadic and, although not usually associated with outbreaks, there is a strong association with preparing and/or eating poultry [3-51. Outbreaks of campylobacter enteritis have been associated with contaminated water and raw milk [2,3]. Fluoroquinolones have good activity against C. jejuni and C. coli with MIC90s generally of 0.25 mg/L [6-8].Campylobacter strains with inherent resistance to nalidixic acid are less susceptible to fluoroquinolones, with a higher MIC90 of 1 mg/L. Fluoroquinolones concentrate within the intestinal mucosa and feces to high levels [9]. Clinical trials with fluoroquinolones have demonstrated a good response, and it was further suggested, and reiterated recently, that fluoroquinolones would be useful for the prophylaxis of travelers’ diarrhea, as thase agents gave symptomatic relief and shortened the duration of dness
EPIDEMIOLOGY OF RESISTANCE TO FLUOROQUINOLONES
The number of Campylobacter strains resistant to the recommended breakpoint concentration of fluoroquinolones (1-4 mg/L depending on the agent and country) differs between countries, and also within countries. Reasons for this include the association with travel, the fact that some countries/laboratories do not test Campylobacter strains for susceptibility to fluoroquinolones, and the veterinary use of quinolones in animals. In 1990, Endtz et al [13] observed that 11% of human isolates of Campylobacter isolated in The Netherlands were resistant to nalidixic acid or ciprofloxacin; by 1991, these authors reported that 30-35% of isolates were resistant. Currently, the reported frequencies of resistance in Spain range from 29% to 82% (Palma de Mallorca [14], Madrid [15], Orense [16,17], San Sebastian [18]). In the UK, there has been a steady increase in the numbers of fluoroquinoloneresistant Campylobacter strains isolated since 1991 [4]. In 1992, Sjogren et al [19] suggested that there had been a small increase in the number of resistant Campylobacter strains over the previous decade and that most cases had been acquired outside Sweden. In Canada, Harnett et al [20], reported that the percentages of Campylobacter isolates resistant to fluoroquinolones were 17%, 10.4% and 14.5% for 1992, 1993 and 1994, respectively;
Corresponding author and reprint requests: Laura J. V. Piddock, Antimicrobial Agents Research Group, Division of Immunity and Infection, The Medical School, University of Birmingham, Edgbaston, Birmingham 815 2lT, UK Tel: +44 121 414 6969
Fax: f 4 4 121 414 6966
E-mail:
[email protected]
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however, there was no information about the country of origin of retail poultry or use of fluoroquinolones. In Thailand [21], it has been suggested that at least 50% of isolates are fluoroquinolone resistant. For the USA, recent data from Minnesota suggest that there was also an increase in the numbers of fluoroquinolone-resistant Campylobacter strains isolated in 1997 compared with 1996 [22]. FAILURE OF FLUOROQUINOLONE THERAPY FOR CAMPYLOBACTER INFECTIONS
Fluoroquinolone-resistant Campylobacter strains arising after treatment for enteritis were first observed in the late 1980s, and several international reports document up to 20% of patients relapsing because of the emergence of a resistant isolate only inhibited by 32 mg/L ciprofloxacin or more [ 11,23-281. Failure of ciprofloxacin therapy of campylobacter infection in an AIDS patient has been reported [28,29]. However, failure of ciprofloxacin therapy does not account for the numbers of ciprofloxacin-resistant strains isolated in microbiology laboratories, and it is clear that many patients have not received any treatment for their illness before presenting to their general practitioner (GP) and therefore it must be presumed that the strain was already fluoroquinolone resistant prior to causing an infection. It has been difficult to obtain published data describing evidence of failure of fluoroquinolones to treat an enteritis with a fluoroquinolone-resistant Campylobacter strain. However, as this infection is usually considered to be self-limiting, it is not known how many patients have been treated. Gaunt (personal communication) performed a small retrospective study in 1998, whereby a questionnaire was sent to the GPs of 39 patients who had had a fluoroquinolone-resistant campylobacter enteritis in 1997; prior to isolation of the resistant strain, one of 39 had received ciprofloxacin 10 days previously to treat a ciprofloxacin-susceptible campylobacter infection and one of 39 had selfmedicated with norfloxacin purchased in Thailand. A further seven patients received ciprofloxacin after a stool specimen was sent to the laboratory; of these, one patient was a clear microbiological failure 10 days after treatment. MECHANISM OF FLUOROQUINOLONE RESISTANCE
In Gram-negative bacteria, D N A gyrase (type I1 topoisomerase) and D N A topoisomerase IV are the primary and secondary targets of fluoroquinolone antibiotics, respectively [30]. Mutations in the genes g y r A and/or parC that encode the A subunits of these two enzymes are the most common mechanisms
observed in clinical isolates of Gram-negative bacteria [31]. Segreti et al [32] purified D N A gyrase from a ciprofloxacin-resistant C. jejuni strain and found that the enzyme was 8-16-fold less sensitive to inhibition by ciprofloxacin than the enzyme isolated from the paired ciprofloxacin-susceptible pre-therapy isolate. In addition, both this resistant isolate and that from the second patient who failed therapy accumulated lower concentrations of ciprofloxacin than the pre-therapy isolates. In strains requiring 16-64 mg/L ciprofloxacin for inhibition, Wang et al identified mutations in g y r A at position 86 (threonine), which is analogous to the site in g y r A in other bacteria shown to give rise to fluoroquinolone resistance [33]. In 1995, Everett et al [34] found the same mutations in human and chicken isolates from the UK, as have Ruiz et a1 [35]. However, mutations in gyrA and MIC values do not correlate, suggesting that other factors are contributing to the overall resistance phenotype. Recently,p a r C of C.jejuni [36] has been described, and a mutation at arginine 139 found in resistant isolates. CROSS-RESISTANCE TO NON-QUINOLONE AGENTS
As a consequence of the high numbers of fluoroquinolone-resistant Campylobacter strains isolated from humans in some countries, it has been proposed that, where antimicrobial chemotherapy is required, the drug of choice should remain erythromycin. However, there have been varying reports of resistance to erythromycin among Carnpylobacter strains, sometimes combined with resistance to fluoroquinolones [37-391. Rautelin et a1 [40] found that five of 30 (17%) consecutive ciprofloxacin-resistant isolates were also erythromycin resistant, but that of 30 erythromycinresistant isolates none were ciprofloxacin resistant, suggesting that erythromycin-resistant isolates are becoming ciprofloxacin resistant. There has been one study of paired isolates where the post-therapy ciprofloxacin-resistant isolate had coincidentally become resistant to both erythromycin and tetracycline [28]. In contrast, in other studies no crossresistance between fluoroquinolones and erythromycin has been observed [4,19,41,42]. A multidrug efflux pump has been described for C. jejuni [43], with overexpression producing strains only susceptible to 16 mg/L of ciprofloxacin and cefotaxime, and 4 mg/L (decreased susceptibility) of chloramphenicol, tetracycline and erythromycin. Transferable resistance to tetracycline and/or kanamycin has been detected in fluoroquinolone-resistant Carnyylobarter strains [18]. Gaunt and Piddock [4] also observed cross-resistance to tetracycline; this may be attributable to transferable resistance in addition to the
Piddock: Quinolone resistance a n d Campylobacter
fluoroquinolone resistance. However, no cross-resistance was seen with erythromycin. Taylor et al [8] have shown that most Campylobacter strains are resistant to novobiocin (MIC 32-512 mg/L). RISK FACTORS ASSOCIATED WITH ACQUIRING FLUOROQUINOLONE-RESISTANTcmwvumcrER STRAINS
For residents of the UK, there is an association between acquisition of ciprofloxacin-resistant Campylobacter strains and recent travel overseas. Gaunt and Piddock [4] found, in a case-control study of 15 cases (compared with a control group of 24 cases with ciprofloxacinsusceptible campylobacter enteritis), that there was a statistically significant association between the acquisition of ciprofloxacin-resistant isolates and travel outside the UK in the 3 months preceding infection. Of the total number of cases (109), 39% were associated with foreign travel, the remainder (61%) having acquired their infection within the UK. As a follow-up, in the recent GP questionnaire (see above), 18 of 39 patients had a history of overseas travel, predominantly to the Iberian peninsula and Thailand, as was previously found (P.N. Gaunt, personal communication). VETERINARY USE OF QUINOLONES AND SELECTION OF FLUOROQUINOLONE-RESISTANT STRAINS
cmwumcm
The predominant reservoir of C. jejuni and C. coli is thought to be poultry [2] (although Campylobacter strains have been isolated from other foods, including pork), and campylobacters are recognized food-borne pathogens. In The Netherlands, flumequine has been used in veterinary medicine since the early 1980s; in 1987, the veterinary fluoroquinolone enrofloxacin was introduced, and in 1988 ciprofloxacin was licensed for human use [44]. By 1993, 29% ofveterinary isolates of Campylobacter were resistant to nalidixic acid, flumequine, enrofloxacin and ciprofloxacin, and it was proposed by Endtz et al [44] that extensive use of quinolones in veterinary medicine in The Netherlands for meat, poultry and milk production contributed to the high frequency of fluoroquinolone-resistant Canipylobacter strains isolated from humans, since in 1982 no resistant strains had been isolated. Jacobs-Reitsma et al [45] have shown in an experimental study that, at slaughter, all Campylobactercolonized broilers exposed to enrofloxacin harbored fluoroquinolone-resistant Cumpylobacter strains. There are no published data on the prevalence of fluoroquinolone-resistant Campylobacter strains in animals, including poultry known to have been exposed to
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fluoroquinolones. However, in animals known not to be exposed to fluoroquinolones, the data suggest that fluoroquinolone resistance is rare [46-481. ISOLATION OF CIPROFLOXACIN-RESISTANT c A M P Y u m c m STRAINS FROMFOOD
Despite the use of enrofloxacin in mainland Europe, there was no license for this agent for veterinary use in the UK until November 1993, and little was used before January 1994. Therefore, the UK could be considered a good ‘control’ to determine the effect of the veterinary use of fluoroquinolones upon the emergence of fluoroquinolone-resistant food-borne pathogens. However, much of the poultry is imported from Europe, and so a hstinction is required between UK-bred birds and those from elsewhere. In a small study by Gaunt and Piddock [4], Campylobacter strains were isolated from 37 of 64 (57.8%) UK-bred birds, with only one strain being ciprofloxacin resistant. In contrast, Campylobacter strains were isolated from 26 of 50 (52%) non-UK chickens, and seven (27%) were ciprofloxacin resistant. A small follow-up study in 1997 demonstrated a similar difference: two of 36 (6%) ciprofloxacin-resistant Campylobacter strains were isolated from UK-bred chicken, compared with 23 of 41 (56%) for non-UK-bred chicken (Gaunt, personal communication). While the two studies are not directly comparable, because of minor differences in methodology, resistance does not yet appear to have emerged in UK poultry following the licensing of enrofloxacin. Indeed, resistance among imported produce is patchy. In the 1997 study, 100 chicken portions were purchased from eight retail outlets: 50 portions from 12 producers in the UK, and 50 portions from five producers in other European countries (Denmark, France and The Netherlands). Resistant strains were found for only two of the 12 UK producers and for only three of the five non-UK producers. Geilhausen et a1 [49] examined 619 Campylobucter isolates from chicken meat produced in Germany, France and The Netherlands, and found that 22 (3.6%) were fluoroquinolone resistant (although the concentration used to determine resistance was not stated). However, pockets of resistance were noted, with four of 10 isolates from one meat batch being resistant to enrofloxacin. ARE CAMPYLOBACTFR STRAINS ISOLATED FROM ANIMALS THE SAME TYPE AS THOSE ISOLATED FROM HUMANS?
There appears to be some dispute as to whether the same types of Campylobucter are isolated from animals
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and humans; however, there are few published studies, and typing of Campylobacter is still at an early stage, with adoption of a universal method not yet achieved. It appears that a combination of Penner serotyping and pulsed-field gel electrophoresis (PFGE) will be used by reference laboratories (J.E. Moore, personal communication). The relationship between PFGE type and antibiotic susceptibility,if any, has yet to be determined. Molecular typing (digestion of chromosomal DNA by restriction endonucleases, and subsequent Southern blotting) of Campylobacter strains from poultry and humans gave rise to two polymorphisms: 78% of the isolates fiom chickens and 29% of the human isolates gave rise to pattern 1; 22% of the isolates from chickens and 71% of the human isolates gave rise to pattern 2 [50]. These data suggest that although the proportions of the isolate types differ between poultry and humans, by ths method there was similarity between isolates of chicken and human origin. In a small study with PFGE to type Cumpylobacter strains, Gielhausen and Mauff [51]found that a few isolates from chickens and humans were identical, but the majority of strains had different profiles. CONSEQUENCES OF INFECTION BY FLUOROQUINOLONERESISTANT CAMPYLOBACTER STRAINS
Laboratories can no longer rely upon susceptibility to nalidixic acid as a method for distinguishing between the different Campylobacter species, as those previously thought to be susceptible, such as C.jejtrni, are increasingly fluoroquinolone resistant. For those individuals with a complicated campylobacter infection caused by a fluoroquinolone-resistant strain, it is unlikely that a fluoroquinolone will eradicate the infection. There is some evidence of failure of fluoroquinolone therapy for fluoroquinolone-resistant campylobacter enteritis, but as not all patients with this infection will receive antimicrobial chemotherapy, it is unclear how many patients have or will be adversely affected. If the treatment of campylobacter infection is essential, susceptibility to the fluoroquinolone of choice should be determined and treatment modified if fluoroquinolone resistance is detected.
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